Nolan Williams

All Publications

• Attenuation of Antidepressant and Anti-Suicidal Effects of Ketamine by Opioid Receptor Antagonism Molecular Psychiatry Williams, N. R., Heifets, B., Bentzley, B., Blasey, C., Sudheimer, K., Hawkins, J., Lyons, D., Schatzberg, A. 2019; In Press
• Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. The American journal of psychiatry Williams, N. R., Heifets, B. D., Blasey, C., Sudheimer, K., Pannu, J., Pankow, H., Hawkins, J., Birnbaum, J., Lyons, D. M., Rodriguez, C. I., Schatzberg, A. F. 2018: appiajp201818020138

  Abstract

  OBJECTIVE: In addition to N-methyl-d-aspartate receptor antagonism, ketamine produces opioid system activation. The objective of this study was to determine whether opioid receptor antagonism prior to administration of intravenous ketamine attenuates its acute antidepressant or dissociative effects.METHOD: In a proposed double-blind crossover study of 30 adults with treatment-resistant depression, the authors performed a planned interim analysis after studying 14 participants, 12 of whom completed both conditions in randomized order: placebo or 50 mg of naltrexone preceding intravenous infusion of 0.5 mg/kg of ketamine. Response was defined as a reduction ≥50% in score on the 17-item Hamilton Depression Rating Scale (HAM-D) score on postinfusion day 1.RESULTS: In the interim analysis, seven of 12 adults with treatment-resistant depression met the response criterion during the ketamine plus placebo condition. Reductions in 6-item and 17-item HAM-D scores among participants in the ketamine plus naltrexone condition were significantly lower than those of participants in the ketamine plus placebo condition on postinfusion days 1 and 3. Secondary analysis of all participants who completed the placebo and naltrexone conditions, regardless of the robustness of response to ketamine, showed similar results. There were no differences in ketamine-induced dissociation between conditions. Because naltrexone dramatically blocked the antidepressant but not the dissociative effects of ketamine, the trial was halted at the interim analysis.CONCLUSIONS: The findings suggest that ketamine's acute antidepressant effect requires opioid system activation. The dissociative effects of ketamine are not mediated by the opioid system, and they do not appear sufficient without the opioid effect to produce the acute antidepressant effects of ketamine in adults with treatment-resistant depression.

  View details for PubMedID 30153752

• High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression. Brain : a journal of neurology Williams, N. R., Sudheimer, K. D., Bentzley, B. S., Pannu, J., Stimpson, K. H., Duvio, D., Cherian, K., Hawkins, J., Scherrer, K. H., Vyssoki, B., DeSouza, D., Raj, K. S., Keller, J., Schatzberg, A. F. 2018

  View details for PubMedID 29415152

• Five Year Follow-Up of Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression BRAIN STIMULATION Williams, N. R., Short, E. B., Hopkins, T., Bentzle, B. S., Sahlem, G. L., Pannu, J., Schmidt, M., Borckardt, J. J., Korte, J. E., George, M. S., Takacs, I., Nahas, Z. 2016; 9 (6): 897-904

  Abstract

  Epidural prefrontal cortical stimulation (EpCS) represents a novel therapeutic approach with many unique benefits that can be used for treatment-resistant depression (TRD).To examine the long-term safety and efficacy of EpCS of the frontopolar cortex (FPC) and dorsolateral prefrontal cortex (DLPFC) for treatment of TRD.Adults (N = 5) who were 21-80 years old with severe TRD [failure to respond to adequate courses of at least 4 antidepressant medications, psychotherapy and ≥20 on the Hamilton Rating Scale for Depression (HRSD24)] were recruited. Participants were implanted with bilateral EpCS over the FPC and DLPFC and received constant, chronic stimulation throughout the five years with Medtronic IPGs. They were followed for 5 years (2/1/2008-10/14/2013). Efficacy of EpCS was assessed with the HRSD24 in an open-label design as the primary outcome measure at five years.All 5 patients continued to tolerate the therapy. The mean improvements from pre-implant baseline on the HRSD24 were [7 months] 54.9% (±37.7), [1 year] 41.2% (±36.6), [2 years] 53.8% (±21.7), and [5 years] 45% (±47). Three of 5 (60%) subjects continued to be in remission at 5 years. There were 5 serious adverse events: 1 electrode 'paddle' infection and 4 device malfunctions, all resulting in suicidal ideation and/or hospitalization.These results suggest that chronic bilateral EpCS over the FPC and DLPFC is a promising and potentially durable new technology for treating TRD, both acutely and over 5 years.

  View details for DOI 10.1016/j.brs.2016.06.054

  View details for Web of Science ID 000387197500013

  View details for PubMedID 27443912

• Deep brain stimulation (DBS) at the interface of neurology and psychiatry JOURNAL OF CLINICAL INVESTIGATION Williams, N. R., Okun, M. S. 2013; 123 (11): 4546-4556

  Abstract

  Deep brain stimulation (DBS) is an emerging interventional therapy for well-screened patients with specific treatment-resistant neuropsychiatric diseases. Some neuropsychiatric conditions, such as Parkinson disease, have available and reasonable guideline and efficacy data, while other conditions, such as major depressive disorder and Tourette syndrome, have more limited, but promising results. This review summarizes both the efficacy and the neuroanatomical targets for DBS in four common neuropsychiatric conditions: Parkinson disease, Tourette syndrome, major depressive disorder, and obsessive-compulsive disorder. Based on emerging new research, we summarize novel approaches to optimization of stimulation for each neuropsychiatric disease and we review the potential positive and negative effects that may be observed following DBS. Finally, we summarize the likely future innovations in the field of electrical neural-network modulation.

  View details for DOI 10.1172/JCI68341

  View details for Web of Science ID 000326611900002

  View details for PubMedID 24177464

• Rigorous Trial Design Is Essential to Understand the Role of Opioid Receptors in Ketamine's Antidepressant Effect. JAMA psychiatry Heifets, B. D., Williams, N. R., Bentzley, B. S., Schatzberg, A. F. 2019

  View details for PubMedID 31042274

• Rigorous Translational Models Are Key to Studying Ketamine's Antidepressant Mechanism: Response to Wang and Kaplin. The American journal of psychiatry Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (5): 412

  View details for PubMedID 31039633

• Robust clinical benefit of multi-target deep brain stimulation for treatment of Gilles de la Tourette syndrome and its comorbidities. Brain stimulation Kakusa, B., Saluja, S., Tate, W. J., Espil, F. M., Halpern, C. H., Williams, N. R. 2019

  View details for PubMedID 30878341

• Interpreting Ketamine's Opioid Receptor Dependent Effect: Response to Sanacora AMERICAN JOURNAL OF PSYCHIATRY Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (3): 249–50

  View details for DOI 10.1176/appi.ajp.2018.18091061r

  View details for Web of Science ID 000462846900011

• Target Population, Dose, and Timing Considerations for Understanding Naltrexone's Subjective Effect: Response to Amiaz. The American journal of psychiatry Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (3): 251–52

  View details for PubMedID 30818989

• Interpreting Ketamine's Opioid Receptor Dependent Effect: Response to Sanacora. The American journal of psychiatry Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (3): 249–50

  View details for PubMedID 30818991

• Target Population, Dose, and Timing Considerations for Understanding Naltrexone's Subjective Effect: Response to Amiaz AMERICAN JOURNAL OF PSYCHIATRY Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (3): 251–52

  View details for DOI 10.1176/appi.ajp.2018.18111231r

  View details for Web of Science ID 000462846900013

• Multimodal characterization of the human nucleus accumbens. NeuroImage Cartmell, S. C., Tian, Q., Thio, B. J., Leuze, C., Ye, L., Williams, N. R., Yang, G., Ben-Dor, G., Deisseroth, K., Grill, W. M., McNab, J. A., Halpern, C. H. 2019

  Abstract

  Dysregulation of the nucleus accumbens (NAc) is implicated in numerous neuropsychiatric disorders. Treatments targeting this area directly (e.g. deep brain stimulation) demonstrate variable efficacy, perhaps owing to non-specific targeting of a functionally heterogeneous nucleus. Here we provide support for this notion, first observing disparate behavioral effects in response to direct simulation of different locations within the NAc in a human patient. These observations motivate a segmentation of the NAc into subregions, which we produce from a diffusion-tractography based analysis of 245 young, unrelated healthy subjects. We further explore the mechanism of these stimulation-induced behavioral responses by identifying the most probable subset of axons activated using a patient-specific computational model. We validate our diffusion-based segmentation using evidence from several modalities, including MRI-based measures of function and microstructure, human post-mortem immunohistochemical staining, and cross-species comparison of cortical-NAc projections that are known to be conserved. Finally, we visualize the passage of individual axon bundles through one NAc subregion in a post-mortem human sample using CLARITY 3D histology corroborated by 7T tractography. Collectively, these findings extensively characterize human NAc subregions and provide insight into their structural and functional distinctions with implications for stereotactic treatments targeting this region.

  View details for PubMedID 31077843

• Comparative effectiveness of neuroablation and deep brain stimulation for treatment-resistant obsessive-compulsive disorder: a meta-analytic study. Journal of neurology, neurosurgery, and psychiatry Kumar, K. K., Appelboom, G., Lamsam, L., Caplan, A. L., Williams, N. R., Bhati, M. T., Stein, S. C., Halpern, C. H. 2019

  Abstract

  The safety and efficacy of neuroablation (ABL) and deep brain stimulation (DBS) for treatment refractory obsessive-compulsive disorder (OCD) has not been examined. This study sought to generate a definitive comparative effectiveness model of these therapies.A EMBASE/PubMed search of English-language, peer-reviewed articles reporting ABL and DBS for OCD was performed in January 2018. Change in quality of life (QOL) was quantified based on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the impact of complications on QOL was assessed. Mean response of Y-BOCS was determined using random-effects, inverse-variance weighted meta-analysis of observational data.Across 56 studies, totalling 681 cases (367 ABL; 314 DBS), ABL exhibited greater overall utility than DBS. Pooled ability to reduce Y-BOCS scores was 50.4% (±22.7%) for ABL and was 40.9% (±13.7%) for DBS. Meta-regression revealed no significant change in per cent improvement in Y-BOCS scores over the length of follow-up for either ABL or DBS. Adverse events occurred in 43.6% (±4.2%) of ABL cases and 64.6% (±4.1%) of DBS cases (p<0.001). Complications reduced ABL utility by 72.6% (±4.0%) and DBS utility by 71.7% (±4.3%). ABL utility (0.189±0.03) was superior to DBS (0.167±0.04) (p<0.001).Overall, ABL utility was greater than DBS, with ABL showing a greater per cent improvement in Y-BOCS than DBS. These findings help guide success thresholds in future clinical trials for treatment refractory OCD.

  View details for PubMedID 30679237

• KETAMINE'S ANTIDEPRESSANT EFFECT IS BLOCKED BY A MU-OPIOID RECEPTOR ANTAGONIST IN HUMANS AND MICE Heifets, B. D., Williams, N., Sudheimer, K., Pankow, H., Blasey, C., Lyons, D., Schatzberg, A. F. LIPPINCOTT WILLIAMS & WILKINS. 2018: 343

  View details for Web of Science ID 000460106500197

• Closing the loop on impulsivity via nucleus accumbens delta-band activity in mice and man. Proceedings of the National Academy of Sciences of the United States of America Wu, H., Miller, K. J., Blumenfeld, Z., Williams, N. R., Ravikumar, V. K., Lee, K. E., Kakusa, B., Sacchet, M. D., Wintermark, M., Christoffel, D. J., Rutt, B. K., Bronte-Stewart, H., Knutson, B., Malenka, R. C., Halpern, C. H. 2018; 115 (1): 192–97

  Abstract

  Reward hypersensitization is a common feature of neuropsychiatric disorders, manifesting as impulsivity for anticipated incentives. Temporally specific changes in activity within the nucleus accumbens (NAc), which occur during anticipatory periods preceding consummatory behavior, represent a critical opportunity for intervention. However, no available therapy is capable of automatically sensing and therapeutically responding to this vulnerable moment in time when anticipation-related neural signals may be present. To identify translatable biomarkers for an off-the-shelf responsive neurostimulation system, we record local field potentials from the NAc of mice and a human anticipating conventional rewards. We find increased power in 1- to 4-Hz oscillations predominate during reward anticipation, which can effectively trigger neurostimulation that reduces consummatory behavior in mice sensitized to highly palatable food. Similar oscillations are present in human NAc during reward anticipation, highlighting the translational potential of our findings in the development of a treatment for a major unmet need.

  View details for PubMedID 29255043

• Influence of gender on inpatient treatment for bipolar disorder: An analysis of 60,607 hospitalisations JOURNAL OF AFFECTIVE DISORDERS Fellinger, M., Waldhoer, T., Blueml, V., Williams, N., Vyssoki, B. 2018; 225: 104–7

  Abstract

  The influence of gender on inpatient treatment patterns in bipolar patients is unclear. The aim of this study is to examine whether differences in length of stay and frequency of inpatient episodes, according to ICD-10 bipolar disorder (BD)-subgroups, exist between men and women.All episodes of a manic (F31.0-2), depressive (F31.3-5) or mixed (F31.6) subtype of BD during an inpatient stay in an Austrian hospital in the period of 2001-2014 were included in this study. Data on episodes was provided by the national statistics agency. Weekly admission rates per 100,000 people were calculated by directly age-standardized rates.The database comprised 60,607 admissions (35.8% men). The number of inpatient episodes was significantly higher (p < 0.001) in women in all BD subgroups. Average length of stay in manic (p < 0.001) and depressive (p < 0.001) episodes was shorter in women compared to men. No difference could be found for mixed episodes.Only aggregated patient data and no single case histories were available for this study.The current study reveals relevant gender differences regarding inpatient treatment patterns, as women were overrepresented in all BD-subgroups. Despite equal life time prevalence, severe mood episodes lead more often to hospitalisations in women. There is a high necessity to further research the underlying causes of these findings.

  View details for PubMedID 28810176

• Modulation of the Neural Circuitry Underlying Trait Hypnotizability With Spaced Continuous Theta-Burst Stimulation Williams, N., Sudheimer, K., Stimpson, K., Duvio, D., Chung, C., DeSouza, D., Jo, B., Williams, L., Yeomans, D., Spiegel, D. NATURE PUBLISHING GROUP. 2017: S508–S509

  View details for Web of Science ID 000416846303052

• Neuroversion: using electroconvulsive therapy as a bridge to deep brain stimulation implantation NEUROCASE Williams, N. R., Sahlem, G., Pannu, J., Takacs, I., Short, B., Revuelta, G., George, M. S. 2017; 23 (1): 26-30

  Abstract

  Parkinson's disease (PD) is a movement disorder with significant neuropsychiatric comorbidities. Electroconvulsive therapy (ECT) is effective in treating these neuropsychiatric symptoms; however, clinicians are reluctant to use ECT in patients with deep brain stimulation (DBS) implantations for fear of damaging the device, as well as potential cognitive side effects. Right unilateral ultra-brief pulse (RUL UBP) ECT has a more favorable cognitive side-effect profile yet has never been reported in PD patients with DBS implants. We present a case series of three patients with a history of PD that all presented with psychiatric decompensation immediately prior to planned DBS surgery. All three patients had DBS electrode(s) in place at the time and an acute course of ECT was utilized in a novel method to "bridge" these individuals to neurosurgery. The patients all experienced symptom resolution (psychosis and/or depression and/or anxiety) without apparent cognitive side effects. This case series not only illustrates that right unilateral ultra-brief pulse can be utilized in patients with DBS electrodes but also illustrates that this intervention can be utilized as a neuromodulatory "bridge", where nonoperative surgical candidates with unstable psychiatric symptoms can be converted to operative candidates in a manner similar to electrical cardioversion.

  View details for DOI 10.1080/13554794.2016.1276605

  View details for Web of Science ID 000399644200005

  View details for PubMedID 28376692

• It Takes Time to Tune Annals of Translational Medicine Bentzley, B. S., Pannu, J., Badran, B. W., Halpern, C. H., Williams, N. R. 2017; In Press
• Optimization of epidural cortical stimulation for treatment-resistant depression. Brain stimulation Williams, N. R., Bentzley, B. S., Hopkins, T., Pannu, J., Sahlem, G. L., Takacs, I., George, M. S., Nahas, Z., Short, E. B. 2017

  View details for PubMedID 28918944

• Description of a Novel, Surgically Implanted Neuromodulatory Technique Known as Bilateral Epidural Prefrontal Cortical Stimulation (EpCS) for Treatment-Resistant Depression (TRD) Journal of Visualized Experiments Williams, N. R., Pannu, J., Bentzley, B. B., Hopkins, T., Badran, B. W., Short, E., George, M. S., Takacs, I., Nahas, Z. 2017; In Press
• Unilateral ultra-brief pulse electroconvulsive therapy for depression in Parkinson's disease. Acta neurologica Scandinavica Williams, N. R., Bentzley, B. S., Sahlem, G. L., Pannu, J., Korte, J. E., Revuelta, G., Short, E. B., George, M. S. 2016

  Abstract

  Electroconvulsive therapy (ECT) has demonstrated efficacy in treating core symptoms of Parkinson's disease (PD); however, widespread use of ECT in PD has been limited due to concern over cognitive burden. We investigated the use of a newer ECT technology known to have fewer cognitive side effects (right unilateral [RUL] ultra-brief pulse [UBP]) for the treatment of medically refractory psychiatric dysfunction in PD.This open-label pilot study included 6 patients who were assessed in the motoric, cognitive, and neuropsychiatric domains prior to and after RUL UBP ECT. Primary endpoints were changes in total score on the HAM-D-17 and GDS-30 rating scales.Patients were found to improve in motoric and psychiatric domains following RUL UBP ECT without cognitive side effects, both immediately following ECT and at 1-month follow-up.This study demonstrates that RUL UBP ECT is safe, feasible, and potentially efficacious in treating multiple domains of PD, including motor and mood, without clear cognitive side effects.

  View details for DOI 10.1111/ane.12614

  View details for PubMedID 27241213

  View details for PubMedCentralID PMC5133197

• Reward circuit DBS improves Parkinson's gait along with severe depression and OCD NEUROCASE Williams, N. R., Hopkins, T. R., Short, E. B., Sahlem, G. L., Snipes, J., Revuelta, G. J., George, M. S., Takacs, I. 2016; 22 (2): 201-204

  Abstract

  A 59-year-old Caucasian man with a past history of Parkinson's disease (PD) status post-bilateral subthalamic nucleus (STN) deep brain stimulation (DBS), who also had treatment-resistant (TR) obsessive-compulsive disorder (OCD), and treatment-resistant depression (TRD), presented for further evaluation and management of his TR OCD. After an unsuccessful attempt to treat his OCD by reprogramming his existing STN DBS, he was offered bilateral ventral capsule/ventral striatum (VC/VS) DBS surgery. In addition to the expected improvement in OCD symptoms, he experienced significant improvement in both PD-related apathy and depression along with resolution of suicidal ideation. Furthermore, the patient's festinating gait dramatically improved. This case demonstrates that DBS of both the STN and VC/VS appears to have an initial signal of safety and tolerability. This is the first instance where both the STN and the VC/VS DBS targets have been implanted in an individual and the first case where a patient with PD has received additional DBS in mood-regulatory circuitry.

  View details for DOI 10.1080/13554794.2015.1112019

  View details for Web of Science ID 000369770400011

  View details for PubMedID 26644268

• NMDA antagonist treatment of depression. Current opinion in neurobiology Williams, N. R., Schatzberg, A. F. 2016; 36: 112-117

  Abstract

  Ketamine is a psychoactive anesthetic agent, which has been approved and utilized for various forms of anesthesia over decades. Recently, ketamine has been demonstrated to have robust and rapid antidepressant effects in individuals with treatment-resistant depression. After more than a decade of research, it is unclear what the mechanisms underlying the novel antidepressant effect are. The consensus has centered on NMDA properties of ketamine as a potential factor in the mechanism for antidepressant action. However, this may be a true but partial explanation of the effects of ketamine as a novel antidepressant. It appears that ketamine influences synaptic plasticity and may promote new synapse formation. From a neurocircuitry perspective, ketamine may exert some of its effects on the anterior cingulate.

  View details for DOI 10.1016/j.conb.2015.11.001

  View details for PubMedID 26687375

• Beyond Neural Cubism: Promoting a Multidimensional View of Brain Disorders by Enhancing the Integration of Neurology and Psychiatry in Education ACADEMIC MEDICINE Taylor, J. J., Williams, N. R., George, M. S. 2015; 90 (5): 581-586

  Abstract

  Cubism was an influential early-20th-century art movement characterized by angular, disjointed imagery. The two-dimensional appearance of Cubist figures and objects is created through juxtaposition of angles. The authors posit that the constrained perspectives found in Cubism may also be found in the clinical classification of brain disorders. Neurological disorders are often separated from psychiatric disorders as if they stemmed from different organ systems. Maintaining two isolated clinical disciplines fractionalizes the brain in the same way that Pablo Picasso fractionalized figures and objects in his Cubist art. This Neural Cubism perpetuates a clinical divide that does not reflect the scope and depth of neuroscience. All brain disorders are complex and multidimensional, with aberrant circuitry and resultant psychopharmacology manifesting as altered behavior, affect, mood, or cognition. Trainees should receive a multidimensional education based on modern neuroscience, not a partial education based on clinical precedent. The authors briefly outline the rationale for increasing the integration of neurology and psychiatry and discuss a nested model with which clinical neuroscientists (neurologists and psychiatrists) can approach and treat brain disorders.

  View details for DOI 10.1097/ACM.0000000000000530

  View details for Web of Science ID 000353879700016

  View details for PubMedID 25340364

  View details for PubMedCentralID PMC4405399

• Oscillating Square Wave Transcranial Direct Current Stimulation (tDCS) Delivered During Slow Wave Sleep Does Not Improve Declarative Memory More Than Sham: A Randomized Sham Controlled Crossover Study BRAIN STIMULATION Sahlem, G. L., Badran, B. W., Halford, J. J., Williams, N. R., Korte, J. E., Leslie, K., Strachan, M., Breedlove, J. L., Runion, J., Bachman, D. L., Uhde, T. W., Borckardt, J. J., George, M. S. 2015; 8 (3): 528-534

  Abstract

  A 2006 trial in healthy medical students found that anodal slow oscillating tDCS delivered bi-frontally during slow wave sleep had an enhancing effect in declarative, but not procedural memory. Although there have been supporting animal studies, and similar findings in pathological groups, this study has not been replicated, or refuted, in the intervening years. We therefore tested these earlier results for replication using similar methods with the exception of current waveform (square in our study, nearly sinusoidal in the original).Our objective was to test the findings of a 2006 trial suggesting bi-frontal anodal tDCS during slow wave sleep enhances declarative memory.Twelve students (mean age 25, 9 women) free of medical problems underwent two testing conditions (active, sham) in a randomized counterbalanced fashion. Active stimulation consisted of oscillating square wave tDCS delivered during early Non-Rapid Eye Movement (NREM) sleep. The sham condition consisted of setting-up the tDCS device and electrodes, but not turning it on during sleep. tDCS was delivered bi-frontally with anodes placed at F3/F4, and cathodes placed at mastoids. Current density was 0.517 mA/cm(2), and oscillated between zero and maximal current at a frequency of 0.75 Hz. Stimulation occurred during five-five minute blocks with 1-min inter-block intervals (25 min total stimulation). The primary outcomes were both declarative memory consolidation measured by a paired word association test (PWA), and non-declarative memory, measured by a non-dominant finger-tapping test (FTT). We also recorded and analyzed sleep EEG.There was no difference in the number of paired word associations remembered before compared to after sleep [(active = 3.1 ± 3.0 SD more associations) (sham = 3.8 ± 3.1 SD more associations)]. Finger tapping improved, (non-significantly) following active stimulation [(3.6 ± 2.7 SD correctly typed sequences) compared to sham stimulation (2.3 ± 2.2 SD correctly typed sequences)].In this study, we failed to find improvements in declarative or performance memory and could not replicate an earlier study using nearly identical settings. Specifically we failed to find a beneficial effect on either overnight declarative or non-declarative memory consolidation via square-wave oscillating tDCS intervention applied bi-frontally during early NREM sleep. It is unclear if the morphology of the tDCS pulse is critical in any memory related improvements.

  View details for DOI 10.1016/j.brs.2015.01.414

  View details for Web of Science ID 000355772300013

  View details for PubMedID 25795621

• Adjunctive triple chronotherapy (combined total sleep deprivation, sleep phase advance, and bright light therapy) rapidly improves mood and suicidality in suicidal depressed inpatients: An open label pilot study JOURNAL OF PSYCHIATRIC RESEARCH Sahlem, G. L., Kalivas, B., Fox, J. B., Lamb, K., Roper, A., Williams, E. N., Williams, N. R., Korte, J. E., Zuschlag, Z. D., El Sabbagh, S., Guille, C., Barth, K. S., Uhde, T. W., George, M. S., Short, E. B. 2014; 59: 101-107

  Abstract

  Previous studies have demonstrated that combined total sleep deprivation (Wake therapy), sleep phase advance, and bright light therapy (Triple Chronotherapy) produce a rapid and sustained antidepressant effect in acutely depressed individuals. To date no studies have explored the impact of the intervention on unipolar depressed individuals with acute concurrent suicidality. Participants were suicidal inpatients (N = 10, Mean age = 44 ± 16.4 SD, 6F) with unipolar depression. In addition to standard of care, they received open label Triple Chronotherapy. Participants underwent one night of total sleep deprivation (33-36 h), followed by a three-night sleep phase advance along with four 30-min sessions of bright light therapy (10,000 lux) each morning. Primary outcome measures included the 17 item Hamilton depression scale (HAM17), and the Columbia Suicide Severity Rating Scale (CSSRS), which were recorded at baseline prior to total sleep deprivation, and at protocol completion on day five. Both HAM17, and CSSRS scores were greatly reduced at the conclusion of the protocol. HAM17 scores dropped from a mean of 24.7 ± 4.2 SD at baseline to a mean of 9.4 ± 7.3 SD on day five (p = .002) with six of the ten individuals meeting criteria for remission. CSSRS scores dropped from a mean of 19.5 ± 8.5 SD at baseline to a mean of 7.2 ± 5.5 SD on day five (p = .01). The results of this small pilot trial demonstrate that adjunctive Triple Chronotherapy is feasible and tolerable in acutely suicidal and depressed inpatients. Limitations include a small number of participants, an open label design, and the lack of a comparison group. Randomized controlled studies are needed.

  View details for DOI 10.1016/j.jpsychires.2014.08.015

  View details for Web of Science ID 000344205700014

  View details for PubMedID 25231629

• Role of functional imaging in the development and refinement of invasive neuromodulation for psychiatric disorders. World journal of radiology Williams, N. R., Taylor, J. J., Lamb, K., Hanlon, C. A., Short, E. B., George, M. S. 2014; 6 (10): 756-778

  Abstract

  Deep brain stimulation (DBS) is emerging as a powerful tool for the alleviation of targeted symptoms in treatment-resistant neuropsychiatric disorders. Despite the expanding use of neuropsychiatric DBS, the mechanisms responsible for its effects are only starting to be elucidated. Several modalities such as quantitative electroencephalography as well a intraoperative recordings have been utilized to attempt to understand the underpinnings of this new treatment modality, but functional imaging appears to offer several unique advantages. Functional imaging techniques like positron emission tomography, single photon emission computed tomography and functional magnetic resonance imaging have been used to examine the effects of focal DBS on activity in a distributed neural network. These investigations are critical for advancing the field of invasive neuromodulation in a safe and effective manner, particularly in terms of defining the neuroanatomical targets and refining the stimulation protocols. The purpose of this review is to summarize the current functional neuroimaging findings from neuropsychiatric DBS implantation for three disorders: treatment-resistant depression, obsessive-compulsive disorder, and Tourette syndrome. All of the major targets will be discussed (Nucleus accumbens, anterior limb of internal capsule, subcallosal cingulate, Subthalamic nucleus, Centromedial nucleus of the thalamus-Parafasicular complex, frontal pole, and dorsolateral prefrontal cortex). We will also address some apparent inconsistencies within this literature, and suggest potential future directions for this promising area.

  View details for DOI 10.4329/wjr.v6.i10.756

  View details for PubMedID 25349661

• Interventional Psychiatry: Why Now? JOURNAL OF CLINICAL PSYCHIATRY Williams, N. R., Taylor, J. J., Kerns, S., Short, E. B., Kantor, E. M., George, M. S. 2014; 75 (8): 895-897

  Abstract

  Interventional psychiatry offers substantial therapeutic benefits in some neuropsychiatric disorders and enormous potential in treating others. However, as interventional diagnostics and therapeutics require specialized knowledge and skill foreign to many psychiatrists, the emerging subspecialty of interventional psychiatry must be more formally integrated into the continuum of psychiatric training to ensure both safe application and continued growth. By establishing training paradigms for interventional psychiatry, academic medical centers can help fill this knowledge gap. The cultivation of a properly trained cohort of interventional psychiatrists will better meet the challenges of treatment-resistant psychiatric illness through safe and ethical practice, while facilitating a more informed development and integration of novel neuromodulation techniques.

  View details for DOI 10.4088/JCP.13l08745

  View details for Web of Science ID 000345530300019

  View details for PubMedID 25191910

• Interventional Psychiatry: How Should Psychiatric Educators Incorporate Neuromodulation into Training? ACADEMIC PSYCHIATRY Williams, N. R., Taylor, J. J., Snipes, J. M., Short, E. B., Kantor, E. M., George, M. S. 2014; 38 (2): 168-176

  Abstract

  Interventional psychiatry is an emerging subspecialty that uses a variety of procedural neuromodulation techniques in the context of an electrocircuit-based view of mental dysfunction as proximal causes for psychiatric diseases.The authors propose the development of an interventional psychiatry-training paradigm analogous to those found in cardiology and neurology.The proposed comprehensive training in interventional psychiatry would include didactics in the theory, proposed mechanisms, and delivery of invasive and noninvasive brain stimulation.The development and refinement of this subspecialty would facilitate safe, effective growth in the field of brain stimulation by certified and credentialed practitioners within the field of psychiatry while also potentially improving the efficacy of current treatments.

  View details for DOI 10.1007/s40596-014-0050-x

  View details for Web of Science ID 000334414300012

  View details for PubMedID 24554501

  View details for PubMedCentralID PMC4021584

• STN vs. GPi Deep Brain Stimulation: Translating the Rematch into Clinical Practice. Movement disorders clinical practice Williams, N. R., Foote, K. D., Okun, M. S. 2014; 1 (1): 24–35

  Abstract

  When formulating a deep brain stimulation (DBS) treatment plan for a patient with Parkinson's disease (PD), two critical questions should be addressed: 1- Which brain target should be chosen to optimize this patient's outcome? and 2- Should this patient's DBS operation be unilateral or bilateral? Over the past two decades, two targets have emerged as leading contenders for PD DBS; the subthalamic nucleus (STN) and the globus pallidus internus (GPi). While the GPi target does have a following, most centers have uniformly employed bilateral STN DBS for all Parkinson's disease cases (Figure 1). This bilateral STN "one-size-fits-all" approach was challenged by an editorial entitled "STN vs. GPi: The Rematch," which appeared in the Archives of Neurology in 2005. Since 2005, a series of well designed clinical trials and follow-up studies have addressed the question as to whether a more tailored approach to DBS therapy might improve overall outcomes. Such a tailored approach would include the options of targeting the GPi, or choosing a unilateral operation. The results of the STN vs. GPi 'rematch' studies support the conclusion that bilateral STN DBS may not be the best option for every Parkinson's disease surgical patient. Off period motor symptoms and tremor improve in both targets, and with either unilateral or bilateral stimulation. Advantages of the STN target include more medication reduction, less frequent battery changes, and a more favorable economic profile. Advantages of GPi include more robust dyskinesia suppression, easier programming, and greater flexibility in adjusting medications. In cases where unilateral stimulation is anticipated, the data favor GPi DBS. This review summarizes the accumulated evidence regarding the use of bilateral vs. unilateral DBS and the selection of STN vs. GPi DBS, including definite and possible advantages of different targets and approaches. Based on this evidence, a more patient-tailored, symptom specific approach will be proposed to optimize outcomes of PD DBS therapy. Finally, the importance of an interdisciplinary care team for screening and effective management of DBS patients will be reaffirmed. Interdisciplinary teams can facilitate the proposed patient-specific DBS treatment planning and provide a more thorough analysis of the risk-benefit ratio for each patient.

  View details for DOI 10.1002/mdc3.12004

  View details for PubMedID 24779023

  View details for PubMedCentralID PMC4000041

• Incidence of sport-related traumatic brain injury and risk factors of severity: a population-based epidemiologic study ANNALS OF EPIDEMIOLOGY Selassie, A. W., Wilson, D. A., Pickelsimer, E. E., Voronca, D. C., Williams, N. R., Edwards, J. C. 2013; 23 (12): 750-756

  Abstract

  Few studies of sport-related traumatic brain injury (TBI) are population-based or rely on directly observed data on cause, demographic characteristics, and severity. This study addresses the epidemiology of sport-related TBI in a large population.Data on all South Carolina hospital and emergency department encounters for TBI, 1998-2011, were analyzed. Annual incidence rate of sport-related TBI was calculated, and rates were compared across demographic groups. Sport-related TBI severity was modeled as a function of demographic and TBI characteristics using logistic regression.A total of 16,642 individuals with sport-related TBI yielded an average annual incidence rate of 31.5/100,000 population with a steady increase from 19.7 in 1998 to 45.6 in 2011. The most common mechanisms of sport-related TBI were kicked in football (38.1%), followed by fall injuries in sports (20.3%). Incidence rate was greatest in adolescents ages 12-18 (120.6/100,000/persons). Severe sport-related TBI was strongly associated with off-road vehicular sport (odds ratio [OR], 4.73; 95% confidence interval [95% CI], 2.92-7.67); repeated head trauma (OR, 4.36; 95% CI, 3.69-5.15); equestrian sport (OR, 2.73; 95% CI, 1.64-4.51); and falls during sport activities (OR, 2.72; 95% CI, 1.67-4.46).The high incidence of sport-related TBI in youth, potential for repetitive mild TBI, and its long-term consequences on learning warrants coordinated surveillance activities and population-based outcome studies.

  View details for DOI 10.1016/j.annepidem.2013.07.022

  View details for Web of Science ID 000327926100002

  View details for PubMedID 24060276

• Unique Case of "Post-Lumbar Puncture Headache" HEADACHE Patel, B. A., Williams, N. R., Pritchard, P. B. 2013; 53 (9): 1479-1481

  Abstract

  Lumbar puncture (LP) is associated with complications that include post-LP orthostatic headache, local bleeding, and subdural hematoma. We report a unique case of a spontaneous frontal epidural hematoma following a therapeutic lumbar puncture in a patient with a history of idiopathic intracranial hypertension. This case highlights the importance of symptomatology in patients following LPs by revealing a rare intracranial presentation that would be devastating if not discovered promptly and appropriately managed.

  View details for DOI 10.1111/head.12005

  View details for Web of Science ID 000325156600008

  View details for PubMedID 23298181

• Sports-Related Concussions PEDIATRIC EMERGENCY CARE Upshaw, J. E., Gosserand, J. K., Williams, N., Edwards, J. C. 2012; 28 (9): 926-935

  Abstract

  During the past decade, awareness of concussions has exploded as both the media and the medical literature have given more focus to this common problem. Concussions after recreational activities, especially athletics, are a frequent complaint in the emergency department. In the past few years, care of these patients has been simplified as grading systems and classifications have been abandoned. However, questions remain as to the best way to rehabilitate these patients to avoid long-term sequelae, especially in children and adolescents. The purpose of this review is to discuss the demographic characteristics, the pathophysiology, definition, clinical characteristics, and management of concussions in children and adolescents.

  View details for DOI 10.1097/PEC.0b013e318267f674

  View details for Web of Science ID 000308673600023

  View details for PubMedID 22940896

• High school coaches perceptions of physicians' role in the assessment and management of sports-related concussive injury. Frontiers in neurology Williams, N., Sas, A., Madey, J., Bodle, J., Scovel, L., Edwards, J. 2012; 3: 130-?

  Abstract

  Sports concussions are an increasingly recognized common type of mild traumatic brain injury (TBI) that affect athletes of all ages. The need for an increased involvement of trained physicians in the diagnosis and treatment of concussion has become more obvious as the pathophysiology and long-term sequelae of sports concussion are better understood. To date, there has been great variability in the athletic community about the recognition of symptoms, diagnosis, management, and physician role in concussion care. An awareness assessment survey administered to 96 high school coaches in a large metropolitan city demonstrated that 37.5% of responders refer their concussed players to an emergency department after the incident, only 39.5% of responders have a physician available to evaluate their players after a concussion, 71.6% of those who had a physician available sent their players to a sports medicine physician, and none of the responders had their player's concussion evaluated by a neurologist. Interestingly, 71.8% of responders stated that their players returned to the team with "return to play" guidelines from their physician. This survey has highlighted two important areas where the medical community can better serve the athletic community. Because a concussion is a sport-inflicted injury to the nervous system, it is optimally evaluated and managed by a clinician with relevant training in both clinical neuroscience and sports medicine. Furthermore, all physicians who see patients suffering concussion should be educated in the current recommendations from the Consensus Statement on Concussion and provide return to play instructions that outline a graduated return to play, allowing the athlete to return to the field safely.

  View details for DOI 10.3389/fneur.2012.00130

  View details for PubMedID 23060851

• Diagnosis, Treatment, and Long-Term Outcomes of Late-Onset (Type III) Multiple Acyl-CoA Dehydrogenase Deficiency JOURNAL OF CHILD NEUROLOGY Pollard, L. M., Williams, N. R., Espinoza, L., Wood, T. C., Spector, E. B., Schroer, R. J., Holden, K. R. 2010; 25 (8): 954-960

  Abstract

  We report 4 children with late-onset (type III) multiple acyl-CoA dehydrogenase deficiency, also known as glutaric aciduria type II, which is an autosomal recessive disorder of fatty acid and amino acid metabolism. The underlying deficiency is in the electron transfer flavoprotein or electron flavoprotein dehydrogenase. Clinical presentations include fatal acute neonatal metabolic encephalopathies with/without organ system anomalies (types I and II) and late-onset acute metabolic crises, myopathy, or neurodevelopmental delays (type III). Two patients were identified in childhood following a metabolic crisis and/or neurodevelopmental delay, and 2 were identified by newborn metabolic screening. Our cases will illustrate the difficulty in making a biochemical diagnosis of late-onset (type III) multiple acyl-CoA dehydrogenase deficiency from plasma acylcarnitines and urine organic acids in both symptomatic and asymptomatic children. However, they emphasize the need for timely diagnosis to urgently implement prophylactic treatment for life-threatening metabolic crises with low protein/fat diets supplemented with riboflavin and carnitine.

  View details for DOI 10.1177/0883073809351984

  View details for Web of Science ID 000279908100003

  View details for PubMedID 20023066

• Relapse rates with long-term antidepressant drug therapy: a meta-analysis HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL Williams, N., Simpson, A. N., Simpson, K., Nahas, Z. 2009; 24 (5): 401-408

  Abstract

  Several long-term double-blind placebo controlled trials have shown prophylactic antidepressant therapy in unipolar depression. The goal of this work was to conduct a meta-analysis that would incorporate the most recent trials and evaluate their overall level of efficacy and relapse prevention over time.We performed a comprehensive literature search. The extracted data from selected studies were used to construct a regression model and evaluate the effect of treatment, time on medication, severity of illness, age, gender, and number of previous episodes.Across 11 maintenance treatment studies, the relapse rate was significantly different at 1 year for active drug (23%) versus placebo (51%). In addition, time on medication significantly affected the relapse rate.Prophylactic antidepressant drug therapy appears efficacious in preventing future relapses across a range of illness severity as well as age. More studies are needed to explore the effects of various acute antidepressant strategies and the direct influence of treatment resistance on relapse outcomes.

  View details for DOI 10.1002/hup.1033

  View details for Web of Science ID 000268116900004

  View details for PubMedID 19526453